JP2002047191A - Water-soluble complex of ginkgo biloba extract and method for preparing water-soluble complex of ginkgo biloba extract - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a water-soluble ginkgo biloba extract by preparing a complex comprising N-methylglucamine coexisting therewith and to provide a method for preparing the complex. SOLUTION: This water-soluble complex of a ginkgo biloba leaf extract comprising the N-methylglucamine coexisting therewith is prepared by adding the N-methylglucamine to an alcohol solution of the ginkgo biloba leaf extract, filtering the resultant individual product and removing the alcohol solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a water-soluble complex of Ginkgo biloba extract and a method for preparing a water-soluble complex of Ginkgo biloba extract.

More specifically, the present invention relates to a water-soluble complex of Ginkgo biloba extract in the presence of N-methylglucamine.

[0003]

BACKGROUND OF THE INVENTION Ginkgo biloba leaves are known to contain a host of hetero-substances consisting of fat-soluble and water-soluble compounds, and Ginkgo biloba extract contains chemical compounds that control cerebral and peripheral vasomotion. It has been studied for many years from the point of view as well as pharmacological and clinical medicine.

[0004] The rough composition of the dry extract used in pharmaceuticals is approximately 24% w / w of heteroside (primarily quercetin-3-O- (6 '"-trans-para-coumaroyl-2" -glucosyl) ) Represented by flavone glycosides consisting of rhamnoside and kaempferol and isorhamnetin-3-O- (6 '"-trans-para-coumaroyl-2" -glucosyl) rhamnoside), about 6% w / w bilobalide and ginkgolide J, A, B and C, composed of about 3-4% w / w of proanthocyanidins (comprising a mixture of anthocyanidins, delphinidin dimers and delphinidin polymers), and inert plant substances which have not yet been clearly identified Is a balancing agent. However, the extract is insoluble in water.

[0005] In order to overcome the above-mentioned disadvantages of not being water-soluble, patent application WO 00/01397 discloses a water-soluble dry extract obtained by targeted ultrafiltration from a hydroalcoholic extract of Ginkgo biloba leaves. are doing.

[0006] Patent application FR-A-2 755 015 discloses a flavonoid extract from Ginkgo biloba leaves that has anti-elastase and anti-inflammatory effects on human gums, along with other ingredients with low content. The application also describes pharmaceutical ingredients, including the extract, for representative treatment of the above-mentioned diseases. Also, the pharmaceutical ingredient can be in the form of a solution. However, the application does not refer to aqueous solutions because the extract is not water-soluble.

[0007]

Although there is still a great demand for extracts of Ginkgo biloba leaves which are particularly rich in flavonoids, low in other components and water-soluble, they are especially soluble in water-soluble Ginkgo biloba No leaf extract has yet been obtained.

An object of the present invention is to produce a water-soluble ginkgo biloba extract by forming a complex in the presence of N-methylglucamine, and to show a method for preparing the same.

[0009]

SUMMARY OF THE INVENTION It has now surprisingly been found that a water-soluble ginkgo biloba extract can be obtained by forming a complex of a ginkgo biloba extract in the presence of N-methylglucamine. . Previously, it was not expected at all that N-methylglucamine would react with many of the components of the extract lacking acid function, so the reaction aimed at forming a water-soluble complex was attempted. I couldn't.

[0010] Accordingly, the present invention, referring to the above reaction,
It is characterized by providing a water-soluble complex of N-methylglucamine coexisting with Ginkgo biloba leaf extract.

[0011] In the method of the present invention, N-methylglucamine is added to an alcohol solution of Ginkgo biloba leaf extract, the obtained solid product is filtered, and the alcohol solvent is removed. Preparing a water-soluble complex of Ginkgo biloba leaf extract.

The term "water soluble" as used herein means at least 1% (weight / volume) soluble in water.

[0013]

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a water-soluble complex of N-methylglucamine coexisting with Ginkgo biloba leaf extract.

The method of the present invention comprises the steps of: a) adding N-methylglucamine to an alcohol solution of Ginkgo biloba leaf extract; b) filtering the solid product obtained in step a); c) Removing the solvent.

The composition obtained by reacting the Ginkgo biloba leaf extract with N-methylglucamine is preferably flavone glycoside 22-45% (weight / weight), ginkgolide 0.1-1.
2% (weight / weight), bilobalide 0.01-5% (weight / weight),
And 3-8% (weight / weight) of proanthocyanidins.

The amount of extract reacting on the dry substrate is N-
Preferably from about 1.5-3.0 times, more preferably up to twice the weight of methylglucamine.

The alcohol solution is typically a saturated aliphatic alcohol solution having 1 to 4 carbon atoms and having a straight or branched chain, such as, for example, methanol, ethanol or isobutanol. .

Preferably, step a) is carried out between a temperature of 0 ° C. and the boiling point of the reaction mixture. More preferably,
This temperature is between 20 and 70 ° C.

Step c) is typically carried out under reduced pressure by evaporating said solvent.

The composition of the water-soluble complex thus obtained is
Preferably, flavone glycoside 15-30% (weight / weight), ginkgolide 0.1-7% (weight / weight), bilobalide 0
-2% (weight / weight), Proanthocyanidins 1-2% (weight
/ Weight), 32-34% N-methylglucamine (weight / weight),
And 25-51.9% (weight / weight) of a water-soluble inert plant substance.

The complex is typically present at 1 and 30% (weight
/ Volume) and the solubility is more typically from 3 to 10% (weight / volume).

[0022]

The following examples are not intended to limit the invention in any way and are intended to illustrate the invention.

Embodiment 1Preparation of starting extract  The extract of Ginkgo biloba leaves used in Examples 2 to 7
The composition having the composition shown in No. 1 was prepared as follows.

[0024]Extracts 564, 597, and 564a  Dried Ginkgo biloba leaves with 60% acetone aqueous solution at 50-60 ℃
Extracted. The solution thus obtained is concentrated and becomes hydrophilic.
, Which was cooled and filtered. Thus gain
Butanol is added to the paste obtained to separate the hydrophobic layer
Removed and concentrated under vacuum to a hydrophilic residue. Hydrophilic residue
Was washed with heptane to remove the alkane layer. Remove the hydrophilic layer
Treated with ethanol, filtered and finally concentrated to dryness. Next
The dried residue was dried in a vacuum oven until it reached a constant weight.
Let dry. The obtained solid product is crushed to a fine powder.
Was.

The various compositions of the extract thus obtained (Table 1) reflect the diversity of the content of the various components of the starting leaves.

[0026]Extract 633  After the removal of butanol, the obtained hydrophilic residue is removed.
Same method as above except that it was extracted with chill acetate
Was executed. Remove hydrophobic layer containing ginkgolide and bilobalide
On the other hand, the resulting hydrophilic layer was treated as described above.
I understood.

[0027]Extracts 632 and 640  These are the methods to prepare the terpene removal extract 633.
Made by purifying the ethyl acetate solution that is removed in
Ginkgolides J, A, B and C
Prepared by quick addition to extract 633 with low lupen content.

[0028]

[Table 1]

Embodiment 2Preparation of the N-methylglucamine / extract complex
1: 2)  Extract 564 of Table 1 with methanol solvent (200 ml) (20
g) into a reactor equipped with a reflux condenser and stirrer
Was. Mix the mixture until the solid extract is completely dissolved.
Stirring was continued. Next, the solution was heated to 60 ° C.
Methylglucamine (10 g) was added. Stir the mixture
Hold the reflux for 15 minutes while cooling to 30 ° C and filter
did. The solution thus obtained under reduced pressure, 50 ° C. or less
Concentrated at the temperature. The resulting solid residue is
The mixture was ground and solidified under reduced pressure at a temperature of 70 ° C. or less.

There was thus obtained 26.74 g of the desired product (89% yield).

The results of analysis of the product are shown in Tables 2 and 3 below.

[0032]

[Table 2]

[0033]

[Table 3]

Embodiment 3The N-methylglucamine / extract
Preparation of the complex of the product (weight ratio 1: 2.25)  Using extract 597 (10.42 g) in Table 1, N-methylgluca
Description of Example 2 above, except that the amount of min was 4.63 g
The method was performed as described above.

Thus, 13.5 g of the desired product were obtained (90% yield).

The results of analysis of the product are shown in Tables 4 and 5 below.

[0037]

[Table 4]

[0038]

[Table 5]

Embodiment 4Preparation of the N-methylglucamine / extract complex (ratio 1
: 2.3)  Extract 564a (Table 10) in Table 1 with methanol solvent (90 ml)
g) into a reactor equipped with a reflux condenser and stirrer.
Was. At room temperature until the solid extract is completely dissolved,
The mixture was kept stirring. Add N-methyl
An aqueous solution of Lucamine (4.35 g) (10 ml of water) was added. Said
The mixture was stirred for 5 minutes and filtered. Before thus obtained
The solution was concentrated under reduced pressure at a temperature of 50 ° C. or lower. As a result
The obtained solid residue is heated at a temperature of 70 ° C. or less under reduced pressure.
And crushed and solidified.

This gave 13.22 g of the desired product (92% yield).

The results of analysis of the products are shown in Tables 6 and 7 below.

[0042]

[Table 6]

[0043]

[Table 7]

Embodiment 5Preparation of the N-methylglucamine / extract complex (ratio 1
: 2)  Extract 632 (54 g) of Table 1 in 849 ml of methanol solvent
Dissolved and added 28 g of N-methylglucamine
Other than the above, the method was performed in the same manner as described in Example 4 above.
Was.

Thus, 77 g of the desired product were obtained (94% yield).

The results of analysis of the product are shown in Tables 8 and 9 below.

[0047]

[Table 8]

[0048]

[Table 9]

Embodiment 6Preparation of the N-methylglucamine / extract complex (ratio 1
: 2)  Extract 633 (10 g) of Table 1 in 150 ml of methanol solvent
Other than dissolving and adding 5 g of N-methylglucamine
Performed the method as described in Example 4 above.

There was thus obtained 13 g of the desired product (86% yield).

The results of the analysis of the products are shown in Tables 10 and 11 below.

[0052]

[Table 10]

[0053]

[Table 11]

Embodiment 7Preparation of the N-methylglucamine / extract complex (ratio 1
: 2)  Extract 1640 of Table 1 (91.23) in 1370 ml of methanol solvent
g) was dissolved, and 45.61 g of N-methylglucamine was added.
Except for this, the method is performed in the same manner as described in Example 2
did.

This gave 123.2 g of the desired product (90% yield).

The results of analysis of the product are shown in Tables 12 and 13 below.

[0057]

[Table 12]

[0058]

[Table 13]

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Claims (6)

[Claims] 1. A water-soluble complex of N-methylglucamine in the presence of a Ginkgo biloba leaf extract. 2. Flavone glycoside 15-30% (weight / weight), ginkgolide 0.1-7% (weight / weight), bilobalide 0
-2% (weight / weight), Proanthocyanidins 1-2% (weight
/ Weight), 32-34% N-methylglucamine (weight / weight),
And a water-soluble inert plant substance 25-51.9% (weight / weight),
The water-soluble complex of N-methylglucamine in the presence of a ginkgo biloba leaf extract according to claim 1, wherein the complex has the following composition. 3. A step of adding N-methylglucamine to an alcoholic solution of Ginkgo biloba leaf extract, and b) Step a)
Filtering the solid product obtained in, and c) removing the alcohol solvent,
A method for preparing a water-soluble complex of Ginkgo biloba leaf extract coexisting with N-methylglucamine. 4. The extract of ginkgo biloba leaves is flavone glycoside 22-45% (weight / weight), ginkgolide 0.1-1.
2% (weight / weight), bilobalide 0.01-5% (weight / weight),
The method for preparing a water-soluble complex of a Ginkgo biloba leaf extract coexisting with N-methylglucamine according to claim 3, characterized in that the composition has the following composition: proanthocyanidin and 3-8% (weight / weight). 5. The method according to claim 1, wherein the amount of the extract in step a) is about 1.5-1.5% by weight of the N-methylglucamine on a dry substrate.
N- according to claim 3, characterized in that it is equal to 3.0 times.
A method for preparing a water-soluble complex of Ginkgo biloba leaf extract coexisting with methylglucamine. 6. The N-cell according to claim 5, wherein the amount of the extract in step a) is equal to about twice the weight of the N-methylglucamine on a dry substrate. A method for preparing a water-soluble complex of Ginkgo biloba leaf extract coexisting with methylglucamine.